The bountiful biological activities of cyclotides

Abstract

Cyclotides are exceptionally stable circular peptides (28-37 amino acid residues) with a unique cyclic cystine knot (CCK) motif that were originally discovered through ethnobotanical investigations and bioassay-directed natural products screenings. They have been isolated from four angiosperm families (Violaceae, Rubiaceae, Curcurbitaceae, and Fabaceae), and they exhibit a wide range of bioactivities including antibacterial/antimicrobial, nematocidal, molluscicidal, antifouling, insecticidal, antineurotensin, trypsin inhibiting, hemolytic, cytotoxic, antitumor, and anti-HIV properties. Reports indicate that the mechanism of cyclotide bioactivity is the ability to target and interact with lipid membranes via the development of pores. Additionally, the nature of their surface-exposed hydrophobic patch and CCK play integral roles in the potency of cyclotides. Their extraordinary stability and flexibility have recently allowed for the successful grafting of analogs with therapeutic properties onto their CCK framework. This achievement, coupled with the myriad of useful naturally occurring bioactivities displayed by cyclotides, makes them appealing candidates in drug design and crop management.

Anionic Host Defence Peptides from the Plant Kingdom: Their Anticancer Activity and Mechanisms of Action

“…In contrast, vaby D (net charge -1) was isolated from Viola abyssinica which grows in extreme habitats and altitudes in the Ethiopian Highlands. The peptide was found to have a broad spectrum of anticancer activity with IC 50 values ranging between 3 μM to 47 μM when directed against a variety of cancers, including hepatocellular carcinoma cells (BEL-7402), and breast carcinoma (MDA-MB-231) [42,73]. More recently, the mechanisms underpinning the activity of the peptide to U-937 GTB lymphoma cells was investigated, which suggested that, in addition to targeting the membranes of these cells, the peptide may be taken up to inflict damage on DNA and other internal targets [74].…”

“…4) [41][42][43], thereby giving the tertiary structure of these molecules amphiphilic characteristics that allow partitioning into biological bilayers [75,76]. However, based on structural differences in their molecular framework, cyclotides can be divided into a number of groups [41,42], including two major subfamilies, generally known as the Möbius and bracelet peptides (Fig. 4) [15,77], and a much smaller group termed chimeric cyclotides [65].…”

“…This topology provides a molecular framework, which includes six backbone loops that define hydrophilic and hydrophobic surface regions (Fig. 4) [41][42][43], thereby giving the tertiary structure of these molecules amphiphilic characteristics that allow partitioning into biological bilayers [75,76]. However, based on structural differences in their molecular framework, cyclotides can be divided into a number of groups [41,42], including two major subfamilies, generally known as the Möbius and bracelet peptides (Fig.…”

“…A number of AHDPs have been identified within the cyclotides, which are a major family of cyclic HDPs [41][42][43] with anticancer action ( Table 2) and a range of other biological activities [41][42][43], which is generally based on the ability of these peptides to interact with target cell membranes [22,23,27]. These peptides are listed in various databases and are now known to be ubiquitous in plants [13,24,25,[44][45][46] [36] and shows molecular dynamic simulations for the interaction of Cn-AMP2 with a model cancer cell membrane.…”

“…4) [41][42][43]. This topology provides a molecular framework, which includes six backbone loops that define hydrophilic and hydrophobic surface regions (Fig.…”